Expression of the B-Cell Receptor Component CD79a on Immature Myeloid Cells Contributes to Their Tumor Promoting Effects

The role of myeloid derived suppressor cells (MDSCs) in promoting tumorigenesis is well-established, and significant effort is being made to further characterize surface markers on MDSCs both for better diagnosis and as potential targets for therapy. Here we show that the B cell receptor adaptor molecule CD79a is unexpectedly expressed on immature bone marrow myeloid cells, and is upregulated on MDSCs generated in multiple different mouse models of metastatic but not non-metastatic cancer. CD79a on MDSCs is upregulated and activated in response to soluble factors secreted by tumor cells. Activation of CD79a on mouse MDSCs, by crosslinking with a specific antibody, maintained their immature phenotype (CD11b+Gr1+), enhanced their migration, increased their suppressive effect on T cell proliferation, and increased secretion of pro-tumorigenic cytokines such as IL-6 and CCL22. Furthermore, crosslinking CD79a on myeloid cells activated signaling through Syk, BLNK, ERK and STAT3 phosphorylation. In vivo, CD79+ myeloid cells showed enhanced ability to promote primary tumor growth and metastasis. Finally we demonstrate that CD79a is upregulated on circulating myeloid cells from lung cancer patients, and that CD79a+ myeloid cells infiltrate human breast tumors. We propose that CD79a plays a functional role in the tumor promoting effects of myeloid cells, and may represent a novel target for cancer therapy.

[1]  S. Terada,et al.  Anti‐IL‐6 receptor mAb eliminates myeloid‐derived suppressor cells and inhibits tumor growth by enhancing T‐cell responses , 2012, European journal of immunology.

[2]  A. Bagg,et al.  CD79a is heterogeneously expressed in neoplastic and normal myeloid precursors and megakaryocytes in an antibody clone-dependent manner. , 2007, American journal of clinical pathology.

[3]  H. Kawamoto,et al.  A revised scheme for developmental pathways of hematopoietic cells: the myeloid-based model. , 2010, International immunology.

[4]  J. Brugge,et al.  IL-6 involvement in epithelial cancers. , 2007, The Journal of clinical investigation.

[5]  L. Lanier,et al.  Inhibition of Immune Responses by ITAM-Bearing Receptors , 2006, Science's STKE.

[6]  D. Printz,et al.  Four-color flow cytometric investigation of terminal deoxynucleotidyl transferase-positive lymphoid precursors in pediatric bone marrow: CD79a expression precedes CD19 in early B-cell ontogeny. , 1998, Blood.

[7]  H. Igarashi,et al.  Cross-linking of B cell receptor-related MB-1 molecule induces protein tyrosine phosphorylation in early B lineage cells. , 1993, Journal of immunology.

[8]  J. Monroe,et al.  Role for Transcription Pax5A Factor in Maintaining Commitment to the B Cell Lineage by Selective Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Receptor Expression1 , 2001, The Journal of Immunology.

[9]  Lionel B Ivashkiv,et al.  Cross-regulation of signaling by ITAM-associated receptors , 2009, Nature Immunology.

[10]  K. Ishihara,et al.  CD79 alpha/CD79 beta heterodimers are expressed on pro-B cell surfaces without associated mu heavy chain. , 1997, International immunology.

[11]  C. Chu,et al.  The expanding roles of ITAM adapters FcRγ and DAP12 in myeloid cells , 2009, Immunological reviews.

[12]  G. Christofori,et al.  Myeloid cells and lymphangiogenesis. , 2012, Cold Spring Harbor perspectives in medicine.

[13]  C. Parish,et al.  Use of the intracellular fluorescent dye CFSE to monitor lymphocyte migration and proliferation. , 2002, Current protocols in immunology.

[14]  Ronald Levy,et al.  Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. , 2010, Blood.

[15]  K. Rajewsky,et al.  The B cell receptor promotes B cell activation and proliferation through a non-ITAM tyrosine in the Igalpha cytoplasmic domain. , 2006, Immunity.

[16]  C. Malone,et al.  The mouse B cell-specific mb-1 gene encodes an immunoreceptor tyrosine-based activation motif (ITAM) protein that may be evolutionarily conserved in diverse species by purifying selection , 2011, Molecular Biology Reports.

[17]  K. Rajewsky,et al.  Interference with Immunoglobulin (Ig)α Immunoreceptor Tyrosine–Based Activation Motif (Itam) Phosphorylation Modulates or Blocks B Cell Development, Depending on the Availability of an Igβ Cytoplasmic Tail , 2001, The Journal of experimental medicine.

[18]  K. Struhl,et al.  Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion , 2011, Proceedings of the National Academy of Sciences.

[19]  Gretchen L. Gierach,et al.  Expression of TGF-β signaling factors in invasive breast cancers: relationships with age at diagnosis and tumor characteristics , 2010, Breast Cancer Research and Treatment.

[20]  R. Kurzrock,et al.  Interleukin‐6 and its receptor in cancer , 2007, Cancer.

[21]  N. Rajewsky,et al.  Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. , 2004, Cell.

[22]  K. Rajewsky,et al.  A B Cell Receptor with Two Igα Cytoplasmic Domains Supports Development of Mature But Anergic B Cells , 2004, The Journal of experimental medicine.

[23]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[24]  D. Gabrilovich,et al.  Myeloid-Derived Suppressor Cells in Human Cancer , 2010, Cancer journal.

[25]  N. Rajewsky,et al.  Survival of Resting Mature B Lymphocytes Depends on BCR Signaling via the Igα/β Heterodimer , 2004, Cell.

[26]  M. Hughson,et al.  CD79a expression in acute myeloid leukemia t(8;21) and the importance of cytogenetics in the diagnosis of leukemias with immunophenotypic ambiguity. , 2005, Cancer genetics and cytogenetics.

[27]  S. Lang,et al.  Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology , 2012, Cancer Immunology, Immunotherapy.

[28]  J. Monroe.  ITAM-mediated tonic signalling through pre-BCR and BCR complexes , 2006, Nature Reviews Immunology.

[29]  J. Monroe,et al.  Analysis of the Individual Contributions of Igα (CD79a)- and Igβ (CD79b)-Mediated Tonic Signaling for Bone Marrow B Cell Development and Peripheral B Cell Maturation1 , 2006, The Journal of Immunology.

[30]  P. Sinha,et al.  Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. , 2012, Seminars in cancer biology.

[31]  D. Esposito,et al.  Lentivirus‐mediated bifunctional cell labeling for in vivo melanoma study , 2009, Pigment cell & melanoma research.

[32]  R Paredes-Aguilera,et al.  Flow cytometric analysis of cell‐surface and intracellular antigens in the diagnosis of acute leukemia , 2001, American journal of hematology.

[33]  M. Wicha,et al.  Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. , 2012, Molecular cell.

[34]  Michelle Collazo,et al.  Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice1 , 2008, The Journal of Immunology.

[35]  M. Cogné,et al.  Structure and expression of the mb‐1 transcript in human lymphoid cells , 1992, Clinical and experimental immunology.

[36]  R. Cardiff,et al.  Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease , 1992, Molecular and cellular biology.

[37]  A. Sica,et al.  Altered macrophage differentiation and immune dysfunction in tumor development. , 2007, The Journal of clinical investigation.

[38]  F. Miller,et al.  Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. , 1992, Cancer research.

[39]  C. Divino,et al.  Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. , 2006, Cancer research.

[40]  M. Slovak,et al.  CD79 alpha expression in acute myeloid leukemia. High frequency of expression in acute promyelocytic leukemia. , 1996, The American journal of pathology.

[41]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[42]  K. Rajewsky,et al.  Cytoplasmic Igα Serine/Threonines Fine-Tune Igα Tyrosine Phosphorylation and Limit Bone Marrow Plasma Cell Formation , 2011, The Journal of Immunology.

[43]  J. Blay,et al.  Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells. , 2011, Cancer research.

[44]  J. Monroe,et al.  Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway. , 2003, Blood.

[45]  K. Pike,et al.  The Cytoplasmic Domain of Igα Is Necessary and Sufficient to Support Efficient Early B Cell Development1 , 2004, The Journal of Immunology.

[46]  Nicholas R. English,et al.  Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer1 , 2001, The Journal of Immunology.

[47]  T. Graf,et al.  Stepwise Reprogramming of B Cells into Macrophages , 2004, Cell.

[48]  S. Steinberg,et al.  A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas , 2013, Cancer Chemotherapy and Pharmacology.

[49]  M. Nussenzweig,et al.  B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta. , 2002, Journal of immunology.

[50]  J. Erler,et al.  Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. , 2009, Cancer cell.

[51]  Dan R. Littman,et al.  Signal transduction by lymphocyte antigen receptors , 1994, Cell.

[52]  K. Rajewsky,et al.  The B Cell Receptor Promotes B Cell Activation and Proliferation through a Non-ITAM Tyrosine in the Igα Cytoplasmic Domain , 2006 .

[53]  C. Kyriakopoulos,et al.  Myeloid-derived Suppressor Cells in Cancer Patients: A Clinical Perspective , 2012, Journal of immunotherapy.

[54]  Y. Katsura.  Redefinition of lymphoid progenitors , 2002, Nature Reviews Immunology.

[55]  Thomas Ried,et al.  Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation , 1999, Nature Genetics.

[56]  D. Carbone,et al.  Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. , 2008, Cancer cell.

[57]  L. Peterson,et al.  Biphenotypic acute leukemia with coexpression of CD79a and markers of myeloid lineage. , 2003, Archives of pathology & laboratory medicine.

[58]  B. Fingleton,et al.  Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. , 2004, Cancer cell.

[59]  Miao-Fen Chen,et al.  Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells , 2012, Journal of Molecular Medicine.

[60]  H. Moses,et al.  Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. , 2010, Cancer research.

[61]  C. Abram,et al.  The Expanding Role for ITAM-Based Signaling Pathways in Immune Cells , 2007, Science's STKE.

[62]  M. Cooper,et al.  Modifications of Igα and Igβ Expression as a Function of B Lineage Differentiation* , 1999, The Journal of Biological Chemistry.

[63]  M. Nussenzweig,et al.  B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-α and Ig-β1 , 2002, The Journal of Immunology.

[64]  C. Reis e Sousa,et al.  Signaling by myeloid C-type lectin receptors in immunity and homeostasis. , 2012, Annual review of immunology.

[65]  J. Byrd,et al.  The B-cell receptor signaling pathway as a therapeutic target in CLL. , 2012, Blood.

[66]  V. Umansky,et al.  T Cells Favoring Tumor Growth CCR 5-Dependent Recruitment of Regulatory Myeloid-Derived Suppressor Cells Mediate Tumor-Infiltrating Monocytic , 2012 .